The Boston Comprehensive Sickle Cell Center (BCSCC) saw major reorganization over the past six years. In this competitive renewal application, while core center leadership remains unchanged, we have elected to build on the strengths of investigators available to BCSCC by making major changes in direction. We maintain the belief that individual investigator projects remain a critical part of the BCSCC mission and therefore have brought new investigators into the BCSCC, refocusing our bench and clinical research activities to include patient services research, translational studies of fetal hemoglobin (HbF) induction, further our understanding the genetic basis of red cell density regulation and examine the role of glucose-6-phosphate dehydrogenase (G6PD) and the modulation of endothelial activity. We are able to do this under current budget restaints because all of our project investigator have independent R01 or equivalent support that provides an important infrastructure upon which to build center activities. We will also build on our past successes in patient recruitment for collaborative clinical trials and we propose a clinical trial aimed at the prevention of hypovitaminosis D and its resulting bone disease. [unreadable] Specific Aims: 1. Carry out novel therapeutic trials in sickle cell anemia and HbSC disease by assembling a large Clinical Core of patients as candidates for Phase I and II clinical trials 2. Conduct innovative studies of: the genetic determinants of sickle erythrocyte hydration; endothelial function and G6PD deficiency; HbF induction by a novel oral agent; improving the delivery of comprehensive preventive services for children with sickle cell disease; and, improving bone health with vitamin D and calcium treatment 3. Provide high quality clinical care for all BCSCC patients with education and counseling for patients, education and research training for medical professionals and genetic testing for hemoglobinopathies 4. Meld the components of the BCSCC into a cohesive system to increase its effectiveness beyond the sum of its individual projects, encouraging interactions with other regional and national sickle cell centers.